3D genome structure reconstruction from chromosomal contact data

2017 ◽  
Author(s):  
◽  
Tuan Anh Trieu
Keyword(s):  
High Resolution ◽  
Genome Structure ◽  
Cell Types ◽  
3D Models ◽  
Graphic User Interface ◽  
Soft Constraints ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Manual Adjustment ◽  
The Relationship

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Different cell types of an organism have the same DNA sequence, but they can function differently because their difference in 3D organization allows them to express different genes and has different cellular functions. Understanding the 3D organization of the genome is the key to understand functions of the cell. Chromosome conformation capture techniques like Hi-C and TCC that can capture interactions between proximal chromosome fragments have allowed the study of 3D genome organization in high resolution and high through-put. My work focuses on developing computational methods to reconstruct 3D genome structures from Hi-C data. I presented three methods to reconstruct 3D genome and chromosome structures. The first method can build 3D genome models from soft constraints of contacts and non-contacts. This method utilizes the concept of contact and non-contact to reconstruct 3D models without translating interaction frequencies into physical distances. The translation is commonly used by other methods even though it makes a strong assumption about the relationship between interaction frequencies and physical distances. In synthetic dataset, when the relationship was known, my method performed comparably with other methods assuming the relationship. This shows the potential of my method for real Hi-C datasets where the relationship is unknown. The limitation of the method is that it has parameters requiring manual adjustment. I developed the second method to reconstruct 3D genome models. This method utilizes a commonly used function to translate interaction frequencies to physical distances to build 3D models. I proposed a novel way to derive soft constraints to handle inconsistency in the data and to make the method robust. Building 3D models at high resolution is a more challenging problem as the number of constraints is small and the feasible space is larger. I introduced a third method to build 3D chromosome models at high resolution. The method reconstructs models at low resolution and then uses them to guide the reconstruction of models at high resolution. The last part of my work is the development of a comprehensive tool with intuitive graphic user interface to analyze Hi-C data, reconstruct and analyze 3D models.

scholarly journals HiCluster: A Robust Single-Cell Hi-C Clustering Method Based on Convolution and Random Walk

2018 ◽  
Author(s):  
Jingtian Zhou ◽  
Jianzhu Ma ◽  
Yusi Chen ◽  
Chuankai Cheng ◽  
Bokan Bao ◽  
...  
Keyword(s):  
Random Walk ◽  
Single Cell ◽  
Clustering Algorithm ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Genome Structure ◽  
Real Data ◽  
Cell Types ◽  
3D Genome ◽  
Cell Clustering

3D genome structure plays a pivotal role in gene regulation and cellular function. Single-cell analysis of genome architecture has been achieved using imaging and chromatin conformation capture methods such as Hi-C. To study variation in chromosome structure between different cell types, computational approaches are needed that can utilize sparse and heterogeneous single-cell Hi-C data. However, few methods exist that are able to accurately and efficiently cluster such data into constituent cell types. Here, we describe HiCluster, a single-cell clustering algorithm for Hi-C contact matrices that is based on imputations using linear convolution and random walk. Using both simulated and real data as benchmarks, HiCluster significantly improves clustering accuracy when applied to low coverage Hi-C datasets compared to existing methods. After imputation by HiCluster, structures similar to topologically associating domains (TADs) could be identified within single cells, and their consensus boundaries among cells were enriched at the TAD boundaries observed in bulk samples. In summary, HiCluster facilitates visualization and comparison of single-cell 3D genomes.

scholarly journals Iteratively improving Hi-C experiments one step at a time

2018 ◽  
Author(s):  
Rosela Golloshi ◽  
Jacob Sanders ◽  
Rachel Patton McCord
Keyword(s):  
Data Quality ◽  
Genome Structure ◽  
Small Samples ◽  
List Type ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Dna Loss ◽  
Measuring Interaction ◽  
Genomic Regions ◽  
And Control

AbstractThe 3D organization of eukaryotic chromosomes affects key processes such as gene expression, DNA replication, cell division, and response to DNA damage. The genome-wide chromosome conformation capture (Hi-C) approach can characterize the landscape of 3D genome organization by measuring interaction frequencies between all genomic regions. Hi-C protocol improvements and rapid advances in DNA sequencing power have made Hi-C useful to diverse biological systems, not only to elucidate the role of 3D genome structure in proper cellular function, but also to characterize genomic rearrangements, assemble new genomes, and consider chromatin interactions as potential biomarkers for diseases. Yet, the Hi-C protocol is still complex and subject to variations at numerous steps that can affect the resulting data. Thus, there is still a need for better understanding and control of factors that contribute to Hi-C experiment success and data quality. Here, we evaluate recently proposed Hi-C protocol modifications as well as often overlooked variables in sample preparation and examine their effects on Hi-C data quality. We examine artifacts that can occur during Hi-C library preparation, including microhomology-based artificial template copying and chimera formation that can add noise to the downstream data. Exploring the mechanisms underlying Hi-C artifacts pinpoints steps that should be further optimized in the future. To improve the utility of Hi-C in characterizing the 3D genome of specialized populations of cells or small samples of primary tissue, we identify steps prone to DNA loss which should be optimized to adapt Hi-C to lower cell numbers.Highlights3 to 5 bullet points (maximum 85 characters, including spaces, per bullet point)Variability in Hi-C libraries can arise from early steps of cell preparationHi-C 2.0 changes to interaction capture steps also benefit 6-cutter librariesArtificial molecule fusions can arise during end repair and PCR, increasing noiseCommon causes of Hi-C DNA loss identified for future optimization

scholarly journals High-resolution TADs reveal DNA sequences underlying genome organization in flies

2017 ◽  
Author(s):  
Fidel Ramírez ◽  
Vivek Bhardwaj ◽  
José Villaveces ◽  
Laura Arrigoni ◽  
Björn A. Grüning ◽  
...  
Keyword(s):  
High Resolution ◽  
Dna Sequences ◽  
Spatial Organization ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Open Chromatin ◽  
Promoter Regions ◽  
Dna Motifs ◽  
3D Genome ◽  
Eukaryotic Chromatin

AbstractEukaryotic chromatin is partitioned into domains called TADs that are broadly conserved between species and virtually identical among cell types within the same species. Previous studies in mammals have shown that the DNA binding protein CTCF and cohesin contribute to a fraction of TAD boundaries. Apart from this, the molecular mechanisms governing this partitioning remain poorly understood. Using our new software, HiCExplorer, we annotated high-resolution (570 bp) TAD boundaries in flies and identified eight DNA motifs enriched at boundaries. Known insulator proteins bind five of these motifs while the remaining three motifs are novel. We find that boundaries are either at core promoters of active genes or at non-promoter regions of inactive chromatin and that these two groups are characterized by different sets of DNA motifs. Most boundaries are present at divergent promoters of constitutively expressed genes and the gene expression tends to be coordinated within TADs. In contrast to mammals, the CTCF motif is only present on 2% of boundaries in flies. We demonstrate that boundaries can be accurately predicted using only the motif sequences, along with open chromatin, suggesting that DNA sequence encodes the 3D genome architecture in flies. Finally, we present an interactive online database to access and explore the spatial organization of fly, mouse and human genomes, available at http://chorogeome.ie-freiburg.mpg.de.

scholarly journals Radiation-induced DNA damage and repair effects on 3D genome organization

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacob T. Sanders ◽  
Trevor F. Freeman ◽  
Yang Xu ◽  
Rosela Golloshi ◽  
Mary A. Stallard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Expression Regulation ◽  
Genome Structure ◽  
Cell Types ◽  
Dimensional Structure ◽  
X Rays ◽  
3D Genome ◽  
Radiation Induced ◽  
The Impact ◽  
3D Genome Structure

AbstractThe three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. We irradiate fibroblasts, lymphoblasts, and ATM-deficient fibroblasts with 5 Gy X-rays and perform Hi-C at 30 minutes, 24 hours, or 5 days after irradiation. We observe that 3D genome changes after irradiation are cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.

scholarly journals Long reads and Hi-C sequencing illuminate the two-compartment genome of the model arbuscular mycorrhizal symbiont Rhizophagus irregularis

2021 ◽  
Author(s):  
Gokalp Yildirir ◽  
Jana Sperschneider ◽  
Mathu C Malar ◽  
Eric CH Chen ◽  
Wataru Iwasaki ◽  
...  
Keyword(s):  
Mycorrhizal Fungi ◽  
Genome Structure ◽  
Arbuscular Mycorrhizal ◽  
Genome Biology ◽  
Rhizophagus Irregularis ◽  
In Planta ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Repeat Content ◽  
Host Microbe Interactions

Chromosome folding links genome structure with gene function by generating distinct nuclear compartments and topologically associating domains (TADs). In mammals, these domains undergo preferential interactions and regulate gene expression, however in fungi the role of chromosome folding in genome biology is unclear. Here, we combine Nanopore (ONT) sequencing with chromatin conformation capture sequencing (Hi-C) to reveal chromosome diversity in a group of obligate plant symbionts with a multinucleate mycelium; the arbuscular mycorrhizal fungi (AMF). We find that phylogenetically distinct strains of the model AMF Rhizophagus irregularis all carry 33 chromosomes. Homologous chromosomes show within species variability in size, as well as in gene and repeat content. Strain-specific Hi-C sequencing reveals that all strains have a 3D genome organization that resembles a checkerboard structure with two distinct (A/B) chromatin compartments. Each compartment differs in the level of gene transcription, regulation of candidate effectors and methylation rate. The A-compartment is more gene-dense and contains most core genes, while the B-compartment is more repeat-rich and has higher rates of chromosomal rearrangement. While the B-compartment is transcriptionally repressed, it has significantly more secreted proteins and in planta up-regulated candidate effectors suggesting a possible host-induced change in chromosome conformation. Overall, this study provides a fine-scale view into the genome biology and evolution of prominent plant symbionts, and opens avenues to study the mechanisms that generate and modify chromosome folding during host-microbe interactions.

scholarly journals GSDB: a database of 3D chromosome and genome structures reconstructed from Hi-C data

2019 ◽  
Author(s):  
Oluwatosin Oluwadare ◽  
Max Highsmith ◽  
Jianlin Cheng
Keyword(s):  
Structure Prediction ◽  
Biological Activities ◽  
Genome Structure ◽  
3D Structure ◽  
Three Dimensional ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Reconstruction Methods ◽  
A Genome ◽  
Structure Reconstruction

ABSTRACTAdvances in the study of chromosome conformation capture (3C) technologies, such as Hi-C technique - capable of capturing chromosomal interactions in a genome-wide scale - have led to the development of three-dimensional (3D) chromosome and genome structure reconstruction methods from Hi-C data. The 3D genome structure is important because it plays a role in a variety of important biological activities such as DNA replication, gene regulation, genome interaction, and gene expression. In recent years, numerous Hi-C datasets have been generated, and likewise, a number of genome structure construction algorithms have been developed. However, until now, there has been no freely available repository for 3D chromosome structures. In this work, we outline the construction of a novel Genome Structure Database (GSDB) to create a comprehensive repository that contains 3D structures for Hi-C datasets constructed by a variety of 3D structure reconstruction tools. GSDB contains over 50,000 structures constructed by 12 state-of-the-art chromosome and genome structure prediction methods for publicly used Hi-C datasets with varying resolution. The database is useful for the community to study the function of genome from a 3D perspective. GSDB is accessible at http://sysbio.rnet.missouri.edu/3dgenome/GSDB

scholarly journals Inferring chromosome radial organization from Hi-C data

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Priyojit Das ◽  
Tongye Shen ◽  
Rachel Patton McCord
Keyword(s):  
Genome Structure ◽  
3D Structure ◽  
Cell Types ◽  
Directed Network ◽  
Chromosome Territories ◽  
Imaging Data ◽  
Microscopy Imaging ◽  
Chromosome Conformation ◽  
Eukaryotic Chromosome ◽  
Radial Organization

Abstract Background The nonrandom radial organization of eukaryotic chromosome territories (CTs) inside the nucleus plays an important role in nuclear functional compartmentalization. Increasingly, chromosome conformation capture (Hi-C) based approaches are being used to characterize the genome structure of many cell types and conditions. Computational methods to extract 3D arrangements of CTs from this type of pairwise contact data will thus increase our ability to analyze CT organization in a wider variety of biological situations. Results A number of full-scale polymer models have successfully reconstructed the 3D structure of chromosome territories from Hi-C. To supplement such methods, we explore alternative, direct, and less computationally intensive approaches to capture radial CT organization from Hi-C data. We show that we can infer relative chromosome ordering using PCA on a thresholded inter-chromosomal contact matrix. We simulate an ensemble of possible CT arrangements using a force-directed network layout algorithm and propose an approach to integrate additional chromosome properties into our predictions. Our CT radial organization predictions have a high correlation with microscopy imaging data for various cell nucleus geometries (lymphoblastoid, skin fibroblast, and breast epithelial cells), and we can capture previously documented changes in senescent and progeria cells. Conclusions Our analysis approaches provide rapid and modular approaches to screen for alterations in CT organization across widely available Hi-C data. We demonstrate which stages of the approach can extract meaningful information, and also describe limitations of pairwise contacts alone to predict absolute 3D positions.

scholarly journals Systematic evaluation of chromosome conformation capture assays

2020 ◽  
Author(s):  
Betul Akgol Oksuz ◽  
Liyan Yang ◽  
Sameer Abraham ◽  
Sergey V. Venev ◽  
Nils Krietenstein ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Cell Types ◽  
Chromosome Conformation Capture ◽  
Chromatin Interaction ◽  
Systematic Evaluation ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Experimental Parameters ◽  
Genome Features ◽  
Multiple Cell

AbstractChromosome conformation capture (3C)-based assays are used to map chromatin interactions genome-wide. Quantitative analyses of chromatin interaction maps can lead to insights into the spatial organization of chromosomes and the mechanisms by which they fold. A number of protocols such as in situ Hi-C and Micro-C are now widely used and these differ in key experimental parameters including cross-linking chemistry and chromatin fragmentation strategy. To understand how the choice of experimental protocol determines the ability to detect and quantify aspects of chromosome folding we have performed a systematic evaluation of experimental parameters of 3C-based protocols. We find that different protocols capture different 3D genome features with different efficiencies. First, the use of cross-linkers such as DSG in addition to formaldehyde improves signal-to-noise allowing detection of thousands of additional loops and strengthens the compartment signal. Second, fragmenting chromatin to the level of nucleosomes using MNase allows detection of more loops. On the other hand, protocols that generate larger multi-kb fragments produce stronger compartmentalization signals. We confirmed our results for multiple cell types and cell cycle stages. We find that cell type-specific quantitative differences in chromosome folding are not detected or underestimated by some protocols. Based on these insights we developed Hi-C 3.0, a single protocol that can be used to both efficiently detect chromatin loops and to quantify compartmentalization. Finally, this study produced ultra-deeply sequenced reference interaction maps using conventional Hi-C, Micro-C and Hi-C 3.0 for commonly used cell lines in the 4D Nucleome Project.

scholarly journals HPV16-LINC00393 Integration Alters Local 3D Genome Architecture in Cervical Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinxin Xu ◽  
Zhiqiang Han ◽  
Yetian Ruan ◽  
Min Liu ◽  
Guangxu Cao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Structural Changes ◽  
Genome Structure ◽  
Genomic Variation ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Cervical Cancer Cells ◽  
Normal Human ◽  
Cervical Cells

High-risk human papillomavirus (hrHPV) infection and integration were considered as essential onset factors for the development of cervical cancer. However, the mechanism on how hrHPV integration influences the host genome structure remains not fully understood. In this study, we performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA-sequencing (RNA-seq) in two cervical cells, 1) NHEK normal human epidermal keratinocyte; and 2) HPV16-integrated SiHa tumorigenic cervical cancer cells. Our results reveal that the HPV-LINC00393 integrated chromosome 13 exhibited significant genomic variation and differential gene expression, which was verified by calibrated CTCF and H3K27ac ChIP-Seq chromatin restructuring. Importantly, HPV16 integration led to differential responses in topologically associated domain (TAD) boundaries, with a decrease in the tumor suppressor KLF12 expression downstream of LINC00393. Overall, this study provides significant insight into the understanding of HPV16 integration induced 3D structural changes and their contributions on tumorigenesis, which supplements the theory basis for the cervical carcinogenic mechanism of HPV16 integration.

scholarly journals Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization

2019 ◽  
Author(s):  
Jacob T. Sanders ◽  
Trevor F. Freeman ◽  
Yang Xu ◽  
Rosela Golloshi ◽  
Mary A. Stallard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Expression Regulation ◽  
Genome Structure ◽  
Cell Types ◽  
Dimensional Structure ◽  
X Rays ◽  
3D Genome ◽  
Radiation Induced ◽  
The Impact ◽  
3D Genome Structure

ABSTRACTThe three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation. 3D genome changes after irradiation were cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibited an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation was not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.

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